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A Phase I Trial of Enzastaurin (LY317615) in Combination With Carboplatin in Adults With Recurrent Gliomas


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Recurrent Gliomas

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Trial Information

A Phase I Trial of Enzastaurin (LY317615) in Combination With Carboplatin in Adults With Recurrent Gliomas


Background:

- Enzastaurin, is a macrocyclic bisindolylmaleimide which disrupts the intrinsic
phosphotransferase activity of conventional and novel PKC isoforms via an interaction
at the ATP binding site, displays selectivity in inhibiting the isoforms. Preclinical
studies demonstrate potent anti-angiogenic activity of enzastaurin and studies in
normal volunteers and solid tumor patients demonstrate the drug is very well tolerated
at doses that achieve a biologically active serum concentration.

- Carboplatin has shown activity as monotherapy in the treatment of recurrent malignant
gliomas in adults and preclinical data generated in our laboratory demonstrates
additive anti-glioma activity with enzastaurin. The safety profile of carboplatin and
the preclinical and clinical data supports its use in combination with enzastaurin in
patients with malignant gliomas.

Objective:

-To establish the maximally tolerated dose of enzastaurin in combination with carboplatin in
patients with refractory primary brain tumors not on any enzyme-inducing anti-epileptic
drugs (nEIAED) and for patients on EIAEDs.

Eligibility:

-Patients with histologically proven malignant glioma are eligible for this study.

Design:

-Patients will be stratified into two groups based on their anti-epileptic medications
(nEIAEDs = Group A, EIAED = Group B)

Group A: Each cycle of therapy will consist of enzastaurin administered daily for 4 weeks
with no breaks between cycles. All patients will receive a 7-day lead-in treatment period
(Cycle 1) consisting of a loading dose of oral enzastaurin on Day 1 at 1125mg, followed by
enzastaurin administered once daily at 500mg for 6 additional days in order to achieve
steady state pharmacokinetics of enzastaurin. The first dose of carboplatin will be
administered on Day 8 of Cycle 1, which will consist of 35 days. Following the lead-in
treatment period, the first combination cycle of enzastaurin and carboplatin (Cycle 2) will
commence as a 28-day cycle. Within each combination cycle, enzastaurin will be orally
administered at 500mg once daily on Days 1 through 28 and carboplatin will be administered
as an intravenous infusion over approximately 30 minutes on Day 1 every 28 days. The
carboplatin dose will be 3 AUC for dose level one. For dose levels 2, 3, and 4, the
carboplatin dose will be 4, 5 and 6 AUC, respectively.

Group B: Each cycle of therapy will consist of enzastaurin administered daily for 4 weeks
with no breaks between cycles. All patients will receive a 7-day lead-in treatment period
(Cycle 1) consisting of a loading dose of oral enzastaurin on Day 1 at 1125mg, followed by
enzastaurin administered once daily at 875mg for 6 additional days in order to achieve
steady state pharmacokinetics of enzastaurin. The first dose of carboplatin will be
administered on Day 8 of Cycle 1, which will consist of 35 days. Following the lead-in
treatment period, the first combination cycle of enzastaurin and carboplatin (Cycle 2) will
commence as a 28-day cycle. Within each combination cycle, enzastaurin will be orally
administered once daily on Days 1 through 28 at 875mg and carboplatin will be administered
as an intravenous infusion over approximately 30 minutes on Day 1 every 28 days. The
carboplatin dose will be 3 AUC for dose level one. For dose levels 2, 3, and 4, the
carboplatin dose will be 4, 5 and 6 AUC, respectively.

National Cancer Institute (NCI) registered this trial with Eli Lilly as sponsor. NCI did
not update the record. In June 2013, NCI transferred the trial to Lilly's clinicaltrials.gov
account and Lilly updated the record with the trial status, study start date, and completion
dates. This trial is not an applicable trial under Food and Drug Administration Amendments
Act of 2007 (FDAAA).

Inclusion Criteria


-INCLUSION CRITERIA:

1. Patients with histologically proven malignant glioma who have progressive disease
following standard treatment will be eligible for this protocol. Malignant glioma
include glioblastoma multiforme (GBM), anaplastic astrocytoma (AA), anaplastic
oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant glioma
NOS (not otherwise specified). Additionally, patients with primitive neuroectodermal
tumors (PNETs) of the central nervous system, progressive low-grade gliomas and
radiographically diagnosed brain stem gliomas will be eligible.

2. Patients must have unequivocal evidence for tumor progression by MRI or CT scan.
This scan should be performed within 14 days prior to registration and on a steroid
dosage that has been stable for at least 5 days. If the steroid dose is increased
between the date of imaging and registration a new baseline MR/CT is required. The
same type of scan, that is., MRI or CT must be used throughout the period of protocol
treatment for tumor measurement.

3. Patients having undergone recent resection of recurrent or progressive tumor will be
eligible as long as all of the following conditions apply:

A. They have recovered from the effects of surgery.

B. Residual disease following resection of recurrent tumor is not mandated for
eligibility into the study. To best assess the extent of residual disease
post-operatively, a CT/ MRI should be done:

- no later than 96 hours in the immediate post-operative period or

- at least 4 weeks post-operatively, and

- within 14 days of registration, and

- on a steroid dosage that has been stable for at least 5 days.

If the 96 hour scan is more than 14 days before registration, the scan needs to be
repeated. If the steroid dose is increased between the date of imaging and
registration, a new baseline MRI/CT is required on a stable steroid dosage for at
least 5 days.

4. Patients must have failed prior radiation therapy and must have an interval of
greater than or equal to 4 weeks from the completion of radiation therapy to study
entry.

5. All patients or their previously designated LAR (Legally Authorized Representative)
(if the patient is deemed by the treating physician to be cognitively impaired or
questionably impaired in such a way that the ability of the patient to give informed
consent is questionable) must sign an informed consent indicating that they are aware
of the investigational nature of this study. Patients will be registered prior to
starting the study.

6. Patients must be greater than or equal to 18 years old, and with a life expectancy
greater than 8 weeks.

7. Patients must have a Karnofsky performance status of greater than or equal to 60.

8. Patients must have recovered from the toxic effects of prior therapy: 2 weeks from
any noncytotoxic investigational agent, 4 weeks from prior cytotoxic therapy, two
weeks from vincristine, 6 weeks from nitrosoureas, 3 weeks from procarbazine
administration, and 1 week for non-cytotoxic agents, for example., interferon,
tamoxifen, thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count).
Any questions related to the definition of non-cytotoxic agents should be directed to
the Study Chair.

9. Patients must have adequate bone marrow function (WBC greater than or equal to
3,000/microl, ANC greater than or equal to 1,500/mm(3), platelet count of greater
than or equal to 100,000/mm(3), and hemoglobin greater than or equal to 10 gm/dl),
adequate liver function (SGOT and bilirubin less than or equal to 2 times ULN), and
adequate renal function (creatinine less than or equal to 1.5 mg/dL and/or creatinine
clearance greater than or equal to 60 cc/min) before starting therapy. These tests
must be performed within 14 days prior to registration. Eligibility level for
hemoglobin may be reached by transfusion.

10. Patients must not have any significant medical illnesses that in the investigator's
opinion cannot be adequately controlled with appropriate therapy or would compromise
the patient's ability to tolerate this therapy.

11. This study was designed to include women and minorities, but was not designed to
measure differences of intervention effects. Males and females will be recruited
with no preference to gender. No exclusion to this study will be based on race.

12. Patients must practice adequate contraception.

13. Prior treatment with an enzyme inducing antiepileptic drug must have been
discontinued at least 14 days prior to study entry for Group A patients.

EXCLUSION CRITERIA:

1. Patients who, in the view of the treating physician, have significant active cardiac,
hepatic, or renal diseases are ineligible.

2. No concurrent use of other standard chemotherapeutics or investigative agents.

3. Prior treatment with platinum-based therapy.

4. Patients known to have an allergic response to mannitol.

5. Patients known to have an active malignancy other than their malignant glioma (except
non-melanoma skin cancer or carcinoma in-situ of the cervix).

6. Patients who have an active infection requiring IV antibiotics.

7. Patients who are pregnant or breast feeding.

8. Patients who have any disease that will obscure toxicity or dangerously alter drug
metabolism.

9. QTc with Bazett's correction that is unmeasurable, or greater than or equal to 460
msec on screening ECG. If a patient has QTc greater than or equal to 460 msec on
screening ECG, a second screen ECG may be repeated at least 24 hours apart. The
average QTc from the 2 screening ECGs must be less than 460 msec in order for the
patient to be eligible for the study.

10. EKG demonstrating clinically significant arrythmia (multifocal premature ventricular
contraction [PVC], bigeminy, trigeminy, ventricular tachycardia, bradycardia) that is
symptomatic or requires treatment (CTCAE Grade 3), or asymptomatic sustained
ventricular tachycardia.

11. Patients who have baseline EKGs suggestive of past or present cardiac ischemia will
not be eligible unless they have an appropriate (as defined by the P.I. of this
trial) negative cardiac work up (that is, echocardiogram, stress test).

12. Patients may not be on systemic anti-coagulants (that is, heparin, warfarin, small
heparin fragments).

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Outcome Measure:

To establish the maximally tolerated dose of enzastaurin in combination with carboplatin in patients with refractory primary brain tumors not on any enzyme-inducing anti-epileptic drugs (EIAED) and for patients on EIAEDs.

Principal Investigator

Joohee Sul, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

070053

NCT ID:

NCT01445119

Start Date:

January 2007

Completion Date:

July 2013

Related Keywords:

  • Recurrent Gliomas
  • Brain
  • Tumor
  • Radiation
  • Antiangiogenesis
  • Chemotherapy
  • Brain Tumor
  • Glioma
  • Glioma

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892